The molecular mechanisms underpinning the unchecked expansion of highly malignant tumor-initiating stem-like cells are not well understood. Here, we identify TBC1D15 as an oncoprotein that can competitively disengage the p53 tumor suppressor from its protective association with Numb, leading to proteolysis of p53 and to the deregulated propagation of tumor stem cell populations. Upon acute nutrient deprivation, TBC1D15 is subjected to autophagic degradation, thereby linking cellular energy and nutrient status to self-renewal capacity.